Dihydrodibenzazocines



United States Patent 3,448,102 DIHYDRODIBENZAZOCINES Harry Louis Yale, New Brunswick, and Francis A. S0-

winski, Edison, N.J., assignors, by mesne assignments, to E. R. Squibb & Sons Inc., New York, N.Y., a corporation of Delaware No Drawing. Original application Mar. 18, 1963, Ser. No. 266,011. Divided and this application Jan. 22, 1965, Ser. No. 432,932

Int. Cl. (307d 41/00, 87/34 US. Cl. 260239 11 Claims ABSTRACT OF THE DISCLOSURE S-[substituted amino-lower alkanoyl]-5,6-dihydrodi- This application is a division of our application Ser. No. 266,011, filed Mar. 18, 1963, and now abandoned.

The invention relates to new basically substituted dihydrodibenzazocines (and their salts) having valuable therapeutic properties, processes for the preparation thereof, and new intermediates useful in such processes.

The therapeutically active compounds of this invention include dihydrodibenzazocines of the general Formula I:

CH=CH /11 12\ wherein A is a lower alkylene radical of at least two carbon atoms, B is a basic saturated nitrogen containing radical of less than twelve carbon atoms, R and R are the same or different and represent hydrogen, halogen, trihalo-lower alkyl and lower alkyl; and salts thereof.

Among the suitable radicals represented by the symbol B are: amino, (lower alkyl)amino; di(lower alkyl)- amino, and basic saturated 5 to 7 membered N-heterocyclic radicals of less than twelve carbon atoms, as exemplified by piperidino, pyrrolidino, morpholino, piperazino, lower alkyl piperazino and homopiperazino.

The terms lower alkyl and lower alkylene as employed herein, include both straight and branched chain radicals of less than 8 carbon atoms. The particularly preferred compounds are those wherein A is a lower alkylene radical of two to three carbon atoms (i.e., ethylene, trimethylene-1,3, and propylene-1,2); B represents di(lower alkyl)amino, morpholino or piperidino, R is in the 3-position and represents hydrogen, chloro or methyl, and R is hydrogen.

As to the salts of the dihydrodibenzazocines, those coming within the purview of this invention include the acid addition salts, particularly, the non-toxic acid-addition salts. Acids useful for preparing the acid addition salts include, inter alia, inorganic acids, such as the hydrohalic acids (e.g., hydrochloric and hydrobromic acid), sulfuric acid and phosphoric acid, and organic acids, such as oxalic, maleic, fumaric, tartaric, citric, pamoic and acetic acid.

The compounds of this invention are therapeutically active compounds which are utilizable as anti-allergic, anticholinergic and analgesic agents. For these purposes they may be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injectables or the like by incorporating the appropriate dose of the compounds with carriers according to accepted pharmaceutical practice.

The compounds of this invention are prepared by a series of reactions as shown by the following equations, wherein R R A and B are as hereinbefore defined:

The substituted 10,1 l-dihydro-5H-dibenzo[a,d]cyc1ohepten-S-ones (compounds II) which are used as initial prod- 3 ucts for preparing the compounds of this invention are described in Journal of Medicinal and Pharmaceutical Chemistry, 4, 335 (1961).

Among the suitable dihydrodibenzocycloheptenones as initial reagents in these reactions may be mentioned: 10,11-dihydro-H-dibenzo[a,d]cyclohepten-S-one; halodihydrodibenzocycloheptenones, such as 1-,2-,3- and 4 chloro 10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5- one and 1-,2,3- and 4-bromo-10,1l-dihydro-SH-dibenzo- [a,d]cyclohepten-5-one; (lower alkyl) substituted dihydrodibenzocycloheptenones, such as 1-,2-,3- and 4- methyl 10,11 dihydro-SH-dibenzo[a,d]cyclohepten-5- one; 1-,2-,3- and 4-ethyl-10,11-dihydro-5H-dibenzo[a,d]- cyclohepten-S-one; 1',2,3- and 4-isopropyl-10,l1-dihydro 5H dibenzo[a,d]cyclohepten-S-one; 1-,2-,3-, and 4 tert.-butyl-l0,l 1-dihydro-5H-dibenz0[a,d] cyclohepten- 5-one;' and 2,4-, 3,6-, 3,9-dimethyl-10,1l-dihydro-SH- dibenzo a,d] cyclohepten-5 one.

In the initial reaction of the process of this invention, the dihydrodibenzocycloheptenones (II) are reacted first with a brominating agent such as molecular bromine, N- bromosuccinimide, N-bromoacetamide, and the like, this reaction preferably being carried out in a solvent like carbontetrachloride or chloroform, whereby III are formed. The III are then treated with pyridine, triethylamine, N-methylmorpholine or like tertiary bases, either alone or in a solvent like toluene, to give IV. The IV are reacted with a salt of hydroxylamine, the reaction preferably being conducted in the presence of a solvent such as pyridine, whereby the corresponding oximes (compounds V) are formed, which are novel compounds of this invention. The oximes are then subjected to a Beckmann rearrangement by treatment with an agent such as polyphosphoric acid. The azocinones (compounds VI) formed, which are novel compounds of this invention, are then reduced to the corresponding azocines (compounds VII), which are also novel compounds of this invention, by treatment with a reducing agent such as lithium aluminum hyride in an organic solvent such as ether or tetrahydrofuran.

Compounds VII are then treated with a basically substituted alkylhalide of the formula: BA halide, wherein B and A are as hereinabove defined, the reaction preferably being conducted in the presence of a basic con densation reagent such as sodamide. The same compounds can alternatively be prepared in two steps, by first reacting with an alkylene dihalide of the formula: (halide-A- halide) and then with a base of the formula: BH.

Another, and preferred, process for preparing the compounds of this invention from the azocines (compounds VII) consists in treating them with a basically substituted acyl halide of the formula: BA'CO-(halide), wherein B is as hereinbefore defined, A is a lower alkylene radical of at least one carbon atom, and the halide is preferably chloro or bromo, whereby the new intermediates of this invention of Formula VII are formed:

wherein R R A and B are as hereinbefore defined. The reaction is preferably conducted in the presence of a basic condensation reagent, such as sodamide and potassium carbonate.

Compounds VIII can also be prepared in two steps from compounds VII by first reacting compounds VII with a halo acid halide of the formula: (halide)-OCA- (halide), wherein A is as hereinbefore defined and the I 4 halides are preferably chloro or bromo, thereby yielding new intermediates of this invention of the Formula IX:

O ,L, I (halide) wherein R R and A are as hereinbefore defined, and reacting the intermediates (compounds IX) with a base of the formula: BH, wherein B is as hereinbefore defined.

Compounds VIII thus obtained, are then reduced with a reducing agent, such as lithium aluminum hydride, to yield the final products of this invention (compounds I).

To prepare the acid-addition salts, the resulting base is treated with the desired acid in the usual manner.

If a substituted dihydrodibenzocyclohepten-S-one is used as a reactant in the above series of reactions the position of the substituent on the resulting azocinone and therefore on the final product will depend on the results of the oximation, two oximes being feasible viz. a synoxime and an anti-oxime, leading to two different azocinones. Thus, Where a 3-substituted dibenzocycloheptenone is interacted upon by hydroxylamine and the oximes produced are then subjected to treatment with agents provoking Beckmann rearrangement, a mixture of 3- and 8-substituted dibenz[b,f]-azocin-6-ones is obtained. These products are then separated by fractional crystallization and the separated products subjected to the remaining steps of the process of this invention. Similarly, a 2-substituted dibenzocycloheptenone yields a mixture of 2- and 9-substituted dibenz-[b,f]azocin-6-ones, and a 1- substituted dibenzocycloheptenone yields a mixture of 1- and lO-substituted dibenz-[b,f] azocin-6-ones.

In addition to their use as intermediates, compounds VIII, as well as the non-toxic acid-addition salts thereof (formed as described hereinbefore for the final products), are therapeutically active compounds which are utilizable as anti-allergic, anticholinergic and analgesic agents. For these purposes they may be administered orally or parenterally in conventional dosage forms such as tablets, capsules, injectables or the like by incorporating the appropriate dose of the compound With carriers according to accepted pharmaceutical practice.

The following examples illustrate the invention (all temperatures being in centigrade). The first example illustrates the preparation of the intermediate compounds VII, as well as its reaction with a BA-halide to give the final compounds of this invention. The remaining examples are directed to alternative methods of preparation of the final compounds of this invention.

Example 1.5-(3-dimethylaminopropyl)-5,6-dihydrodibenz[b,f]azocine dihydrochloride (a) Preparation of dibenzo[a,d]cyclohepten-5-one.- A mixture of 128.9 g. of 10,11-dihydrodibenzo[a,d]- cyclohepten-S-one, 110.0 g. of N-bromosuccinimide, and 750 ml. of carbontetrachloride is stirred and heated under reflux for 18 hours. The reaction mixture is filtered and the filtrate concentrated to give a residue of IO-bromo- 10,11-dihydrodibenzo[a,d]cyclohepten-S-one. This is dissolved in 193 ml. of pyridine and stirred and heated under reflux for 2 hours and poured into cold dilute hydrochloric acid. The product is filtered and dried to give about 78.4 g. (61%) of dibenzo[a,d]cyclohepten-5-one, M.P. about 89-91".

(b) Preparation of dibenzo[a,d1 cyclohepten 5 one oxi-me.A mixture of 20 g. of the product from (a), 10 g. of hydroxylamine hydrochloride and 60 ml. of pyridine is heated under reflux for 20 hours. The pyridine is patrially removed, the residue poured into dilute hydrochloric acid and petroleum ether is added. The mix ture is allowed to cool in a refrigerator for two hours and the solid crystalline product is filtered 01f and dried. After crystallization from petroleum ether, 11 grams (46%) of a product melting at about 187-188 is obtained.

Preparation of dibenzo['b,f]azocin-6-one.T0 1400 g. of stirred polyphosphoric acid at 100 is added 39.7 g. of the product from (b). The temperature is raised to 125 during 0.25 hour, maintained at 125 for 0.5 hour and the mixture poured into ice Water. The solid is filtered, Washed and dried to give about 35.7 g. (90%) of product, M.P. about 263-264 (dec.).

(d) Preparation of 5,6-dihydrodibenz[b,f]azocine: (1) Reduction of dibenzo[b,f]azocin-6-one.-To 11.4 g. of lithium aluminum hydride in 1000 ml. of anhydrous ether is added 22.1 g. of the product from (c) in small portions. The mixture is heated under reflux for 12 hours, decomposed and filtered. The filtrate is dried and concentrated to give 20 g. of crude product. Recrystallization from petroleum ether yields about 16.4 g. of product (79%) melting about 108-109.

(e) Preparation of -(3-dimethylaminopropyl)-5, 6-dihydrodibenz[b,f]azocine.A mixture of 12.4 of 5,6-dihydrodibenz[b,f]azocine, 2.9 g. of sodamide and 400 ml. of anhydrous xylene is stirred and heated under reflux for 1 hours, cooled, 12.1 g. of S-dimethylaminopropyl chloride added dropwise and heating continued for 5 hours. The mixture is filtered, the filtrate cooled and extracted with 500 ml. of 5% hydrochloric acid. The acid solution is treated with an excess of solid potassium carbonate and the base separated by means of ether. The ether solution is dried, concentrated and the residue distilled to give about 11.6 g. (66%) of 5-(3-dimethylaminopropyl)5,6-dihydrodibenz[b,fJazocine, BJP. about 162-164 (0.08 mm).

(f) Preparation of 5-(3-dimethylaminopropyl)-5,6-dihydrodibenz[b,f]azocine -dihydrochloride.To an icecooled solution of 11.2 g. of the product from (e) in 150 ml. of anhydrous ether is added dropwise 24.1 ml. of 3.65 N ethereal hydrogen chloride. The solid is triturated in acetone and recrystallized from acetonitrileether to give about 10.0 g. (71%) of 5-(3-dimethylaminopropyl) 5,6 dihydrodibenz[b,f azocine dihydrochloride, M.P. about 188-189 (dec.).

Similarly by substituting an equivalent amount of the following substituted 10,11-dihydrodibenzo[a,d]cyclohepten-5-ones for the 10,11-dihydrodibenzo[a,d]cyclohepten-S-one in step (a) of Example I, the indicated substituted 5 (3 dimethylaminopropyl) 5,6 dihydrodibenz[b,f] azocines are formed:

Substituted 10,11-dihydrodibenzo Substituent [a,d] cycloheptene-S-one: in product l-chloro land -chloro. 2-chloro 2- and 9-chloro. 3-methyl 3- and S-methyl. 4-tertiary butyl 4- and 7-tertiary butyl. 4-bromo 4- and 7-bromo. l-ethyl 1- and IO-ethyl. 2-isopropyl 2- and 9-isopropyl.

Example 2.--5- (2-morpholinoethyl -5,6-dihydrodibenz [b,f azocine oxalate (a) Preparation of 5-(2-chloroacetyl)-5,6dihydrodibenz[b,f]azocine.A mixture of 4.2 g. of 5,6-dihydrodibenz[b,f]azocine, 2.3 g. of chloroacetyl chloride, 2.8 g. of potassium carbonate and 100 ml. of xylene is heated under reflux for three hours. The mixture is cooled and filtered. The xylene is distilled under reduced pressure and the residue is recrystallized from petroleum ether to yield about 5 g. of 5-chloroacetyl-5,6-dihydrodibenz [b,fJazocine.

(b) Preparation of 5-(Z-morpholinoacetyl)-5,6-dihydrodibenz[b,f]azocine, hydrochloride.-A mixture of 6 g. of the product from (a), 3.5 g. of morpholine and 50 ml. of alcohol is heated under reflux for 10 hours. The alcohol is removed and the residual oil treated with ether and sodium bicarbonate solution. The ether is separated, dried and an ethereal solution of hydrogen chloride added. The precipitated salt is filtered ofl? to yield about 4.5 g. of crude product.

By recrystallization from a mixture of acetone and petroleum ether 3 g. (38%) of pure product is obtained.

(0) Preparation of 5-[2-(morpholinoethyl)-5,6-dihy drodibenz[b,f]azocine.--A mixture of 7 g. of the product from (b), 1.5 g. of lithium aluminum hydride and ml. of anhydrous ether is heated and stirred for 16 hours. The mixture is decomposed, the ether layer separated, dried and concentrated to give 5 g. of an oil; this, in ether and an ethereal solution of oxalic acid gives the crude oxalate. Recrystallization from methanol gives 5 g. (58%) of pure 5-(2-morpholinoethyl)-5,6-dihydrodibenz[b,f] azocine oxalate.

Similarly by substituting an equivalent amount of the following substituted 5,6-dihydrodibenz[b,-f]azocines for the 5,6-dihydrodibenz[b,f]azocine in Example 2, step (a), and following the procedure of Example 2, the indicated substituted base and oxalic acid salt are formed:

Substituted 5 ,6-dihydrodibenz Su-bstituent [b,f] azocine: in product l-chloro l-chloro. 2-chloro 2-chloro. 3-methyl 3-methyl. 4-tertiary butyl 4-tertiary butyl. 4-bromo 4-bromo. l-ethyl l-ethyl. 2-isopropyl 2-isopropyl. 9-chloro 9-chloro. 7-tertiary butyl 7-tertiary butyl.

Example 3 .5-(2-piperidinoethyl -5,6-dihydrodibenz [b,f] azocine oxalate '(a) Preparation of 5 (2-piperidinoacetyl)-5,6-dihydrobenz[b,f]azocine.-A mixture of 5.7 g. of the product from Example 2(a), 2 g. of piperidine and 50 ml. of alcohol is reacted as in Example 2(b) to yield about 3.5 g. of 5 (2 piperidinoacetyl) 5,6 dihydrodibenz[=b,f] azocine.

(b) 5 (2 piperidinoethyl) 5,6 dihydrodibenz [-b,f]azocine -oxalate.A mixture of 5 g. of the product from (a), 1.5 g. of lithium aluminum hydride and 50 ml. of anhydrous ether is reacted as in Example 2*(c) to give about 4.5 g. of 5-(2-piperidinoethyl)-5,6-dihydrodibenz [b,fJazocine oxalate.

Similarly by substituting an equivalent amount of the following substituted 5,6-dihydrodibenz[b,f]azocines for the 5,6-dihydrodibenz[b,f]azocine in Example 3, step (a), and following the procedure of Example 3, the indicated substituted base and oxalic acid salt are formed:

Substituted 5,6-dihydrodibenz Substituent [b,f] azocine: in product l-chloro l-chloro. 2-chloro 2-chloro. 3-methyl 3-methyl. 4'tertiary butyl 4- ertiary butyl. 4- bromo 4-br0m0. l-ethyl l-ethyl. 2-isopropyl 2-isopropyl. 9-chloro 9-chloro. 7-tertiary butyl 7-tertiary butyl. 8-methyl 8-methyl.

Example 4.-5-(3-morpholinopropyl)-5,6-dihydrodibenz [b,fJazocine maleate (a) 5-(3- chloropropionyl)-5,6-dihydrodibenz[b,f] azocine.A mixture of 8.3 g. of 5,6-dihydrodibenz[b,f]

azocine, 5.1 g. of fi-chloropropionyl chloride and 5 .6 g. of potassium carbonate in 100 ml. of benzene is heated under reflux for three hours. The mixture is cooled and filtered. The benzene is distilled to yield 10 grams (95%) of 5-(3-chloropropionyl)'-5,6-dihydrodibenz[b,f] azocine.

(b) Preparation of 5-(3-morpholinopropyl)-5,6-dihydrodibenz [b,f] azocine oxalate.A mixture of 6 g. of the product from (a), 3.5 g. of morpholine and 50 ml. of alcohol is reacted as in Example 2(b) to yield about 5.5 g. of 5-(3-morpholinopropyl)-5,6-dihydrodibenz[b,f] azocine.

Preparation of -(3-morpholinopropy1)-5,6-dihydrodibenz[b,f]azocine maleate.-A mixure of 3.3 g. of the product from (b), 0.75 gram of lithium aluminum hydride and 100 ml. of anydrous ether is reacted as in Example 2(c). The ether solution of the basic product is treated with an ethereal solution of maleic acid to yield about 4 g. (89%) of pure 5-(3-morpholinopropyl)-5,6- dihydrodibenz[b,f] azocine maleate.

Example 5 .5- 3-dimethylaminopropyl -5 ,6- dihydrodibenz [b,f] azocine oxalate (a) 5-(3-dirnethylaminopropionyl)-5,6-dihydrodibenz ['b,f]azocine.From 6 g. of the product from 4(a), 2.5 g. of dimethylamine and 50 ml. of alcohol by the procedure of Example 2(b), there is obtained 5-(3-dirnethy1- aminopropionyl -5,6-dihydrodibenz [b,f] azocine.

(b) Preparation of 5-(3-dimethylaminopropyl)-5,6- dihydrodibenz[ b,f]azocine oxalate.From 4.6 g. of the product from, (a), 1.4 g. of lithium aluminum hydride and 50 ml. of anhydrous ether, by the procedure of Example 2(c), there is obtained about 3.4 g. of 5-(3-dimethylaminopropyl)-5,6-dihydrodibenz[b,f]azocine oxalate.

Example 6.5-(3-piperidinopropyl)-5,6-dihydrodibenz [b,f] azocine hydrochloride (a) Preparation of 5-(3-piperidinopropionyl)-5,6- dihydrodibenz[b,f]azocine.-A mixture of 6.0 g. of the product from 4(a), 2.5 g. of piperidine and 50 ml. of alcohol is reacted by the procedure of Example 2(b). The free base is converted into the oxalate salt in the usual manner.

(b) Preparation of 5-(3-piperidinopropyl)-5,6-dihydrodibenz[b,f]azocine hydrochloride-From a mixture of 3.5 g. of the product from (a), 1.0 g. of lithium aluminum hydride and 50 ml. of anhydrous ether about 2.7 grams of 5-(3-piperidinopropyl)-5,6-dihydrodibenz[b,f] azocine hydrochloride are obtained.

Example 7 .-5- 3- (N -methylpiperazino propyl]-5,6-

dihydrodibenz [b,f] azocine dihydrochloride (a) Preparation of 5-[3-(N -methylpiperazino)propionyl] -5,6-dihydrodibenz [b,f] azocine hydrochloride.- From a mixture of 6.0 g. of the product from 4(a), 3.0 grams of N-methylpiperazine and 50 ml. of alcohol, according to the procedure described in Example 2(a) is obtained 5- 3- (N -methylpiperazino propionyl] -5,6-dihydrodibenz[b,f]azocine. This base is converted into a salt with 1 mole of hydrochloric acid.

(b) Preparation of 5-[3- (N -methylpiperazino) propyl] 5,6-dihydrodibenz[b,f]azocine dihydrochloride-From a mixture of 7.3 grams of the base from (a), 1.8 grams of lithium aluminum hydride and 70 ml. of anhydrous tetrahydrofuran, there is obtained 3.0 grams of the dihydrochloride of 5-[3-(N -methylpiperazino)propyl]-5,6- dihydrodibenz[b,f]azocine.

Example 8.-5 [3-(N -methylhomopiperazino)ethyl] 5,6-dihydrodibenz [b,f] azocine dimaleate (21) Preparation of 5 [3 -N methylhomopiperazino)- acetyl]-5,6-dihydrodibenz[b,f]azocine maleate.By subsitituting an equivalent amount of N -methylhomopiperazine for the morpholine in Example 2(b), there is obtained 5 3- (N -methylhomopiperazino acetyl] -5 ,6-dihydrodibenz[b,f]azocine. The base, in acetone, with an acetone solution of maleic acid, gives the maleate.

(b) Preparation of 5-[3-(N -methylhomopiperazino) ethyl]-5,6-dihydrodibenz[b,f] azocine dimaleate.-By substituting an equivalent amount of the product from (a) for the 5-(Z-morpholinoacetyl)-5,6-dihydrodibenz[b,f] azocine in Example 2(c), there is obtained 5-[3-(N methylhomopiperazino)ethyl] 5,6 dihydrodibenz[b,f] azocine. This base with maleic acid, as in (a) gives the maleate salt.

Example 9.-5-(3-methylaminopropyl)5,6-dihydrodibenz [b,f]azocine maleate (a) Preparation of 5-(3-methylaminopropionyl) -5,6-dihydrodibenz[b,f]aZ0cine.By replacing the 2.5 g. of dimethylamine in Example 5(a) with 6.2 g. of methylamine and proceeding as in Example 3(a), there is obtained 2.3 g. of 5-(3-methylarninopropionyl)-5,6-dihydrodibenz[b,f]azocine.

(b) Preparation of 5-(3-methylaminopropyl)-5,6-dihydrodibenz[b,f]azocine.-Substituting 4.4 g. of the product from (a) for the 4.6 g. of 5-(3-dimethylaminopropionyl)-5,6-dihydrodibenz[b,f]azocine and maleic acid for the oxalic acid in Examples 5(b), there is obtained 5- (3 methylaminopropyl) 5,6 dihydrodibenz[b,f]azocine maleate, M.P. 112-1 14.

This invention may be variously otherwise embodied within the scope of the appended claims.

What is claimed is:

1. A compound of the formula wherein R and R are each selected from the group consisting of hydrogen, halogen and lower alkyl.

2. 5,6-dihydrodibenz[b,f] azocine.

3. A compound selected from the group consisting of bases of the formula:

wherein A is lower alkylene, R is selected from the group consisting of amino, (lower alkyl) amino, di(lower alkyl amino, piperidino, pyrrolidino, monpholino, piperazino, (lower alkyl) piperazino, and homopiperazino, R and R are each selected from the group consisting of hydrogen, halogen and lower alkyl; and non-toxic acid-addition salts thereof.

4. 5-[di(l-ower alkyl)amino(lower alkanoyl)]-5,6-dihydrodibenz[b,f]azocine.

5. A non-toxic acid-addition salt of the compound of claim 4.

6. 5 (3-dimethylaminopropionyl)-5,6-dihydrodibenz- [b,f] -azocine.

7. A non-toxic acid-addition salt of the compound of claim 6.

8. A non-toxic acid-addition salt of 5-(2-morpholinoacetyl -5,6-dihydrodibenz [-b,f] azocine.

9. A non-toxic acid-addition salt of 5-(3-monpholinopropionyl)-5,6-dihydrodibenz['b,f]azocine.

9 10 10. A compound of the formula References Cited E UNITED STATES PATENTS R1 R, 3,025,288 3/1962 Schindler.

\ 5 3,038,896 6/1962 Habichtet a1.

N 0H, 3,084,155 4/1963 Winthrop 260239.3

=0 I ALTON D. ROLLINS, Primary Examiner. A-(hahde) wherein R and R are each selected from the group con- 10 CL sisting of hydrogen, halogen and lower alkyl, and A is lower alkylene. 260239.3, 247.2, 247.5, 268, 293, 294, 326.3, 316.81,

11, S-(chloroacetyD-S,6-dihydrodibenz[b,f]azocine,

22 3 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 448, 102 Dated June 3 1969 Invent0r(8) Harrv Louis Yale and Francis A, sowinski It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

T In column 2, formula V, those portions of the formula reading CH=CH CH=CH R R should read R I l MC V C/ H bLOH NOH Column 3, line 56, "VII" should read VIII Column 5, line 1, "patrially" should read partially and on line 25, after "12.4" insert g. and on line 28, "hours" should read hour Column 8, line 57, "R" should read smman A SEALED mm 191970 (SEAL) Attest:

Edward M. Fletcher. Ir- Attesting Officer WEI-LIAM E. sum, as.

Commissioner of Patents 

